S-Isomer of 2- piperidine and Other Dermal Anesthetic Agents

ABSTRACT

The present invention relates to the S-isomers of anesthetic compounds, the methods of treatment therewith, the compounds being useful for inducing local anesthesia, analgesia and sleep.

This application is a Divisional of U.S. Ser. No. 11/236,263 filed Sep.27, 2005, which claims priority of U.S. Provisional Application Ser. No.60/613,386 filed Sep. 27, 2004, the disclosures of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to new nerve membrane stabilizingcompounds and to methods of inducing local, topical or dermalanesthesia, by administering a composition containing at least one suchchemical entity that has such penetration properties that it in a shortperiod of time can reach the site of action on the nerve ending or anerve in a concentration that will block the initiation or conduction ofnerve impulses for a long period of time. The invention also relates tocompositions containing at least one of the compounds of the presentinvention that are particularly useful for ocular and dermal anesthesiaand for other forms of local anesthesia, such as for exampleinfiltration anesthesia and nerve blocks.

The chemical compounds of this invention also have pharmacologicalproperties that render the compounds useful in preventing and treatingpain. The compounds of the present invention are useful for theprevention of pain in connection with certain medical procedures such asthe insertion of an injection needle, surgical procedures and for thetreatment of pain such as in connection with the above mentioned medicalprocedures, insect bites, sunburn, neuropathic pain and for thetreatment of shingles and urogenital pain, including hemorrhoids.

Induction of anesthesia and prevention and treatment of pain using thecompounds of this invention may be achieved by applying compositionscontaining the chemical entities on the skin or by applying compositionscontaining the chemical entities on mucosal membranes or by injectingsolutions of the chemical entities to infiltrate biological tissues withthe solutions or by injecting solutions of the chemical entities in theanatomical vicinity of nerves, thereby allowing the chemical entities topenetrate the biological tissues and cause dermal anesthesia, topicalanesthesia, infiltration anesthesia and/or nerve blocks. Ocular, nasal,rectal, urogenital and other parenteral routes of administration arealso contemplated.

Thus, the present invention provides effective methods for treatinghumans and animals with topical, dermal and local anestheticcompositions, while reducing undesirable side effects, for example localburning and itching and particularly tissue toxicity resulting innecrosis.

The compounds may also be used to treat conditions, comprisingconvulsions, hiccup and cardiac arrhythmias and can be used to inhibitsodium and potassium ion fluxes over cell membranes in the body.

The present invention relates to optically active S-isomers of acompound having the formula:

or a pharmaceutically acceptable salt, base, or mixture thereof, whereinn is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or anoxygen atom, the (CH₂)_(n) group having a straight or branched chain, Brepresents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms ora group of the formula

in which R₃ and R₄ may independently be selected from the groupconsisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radicalcontaining 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen,A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenylradical substituted by at least one substituent in the ortho, metaand/or para position, and R₁ represents a hydrogen, or a lower alkyl orhydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleusis attached at the 2-, 3-, or 4-position.

The present invention also relates to a compound namedS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine, hereinafter calledS-LAC-34 and to the processes for preparing S-LAC-34 and the saltsthereof, to methods for using S-LAC-34 as a local anesthetic agent, tomethods for using S-LAC-34 as an analgesic agent, and to pharmaceuticalformulations containing S-LAC-34.

The invention also refers to compositions, containing at least one ofthe chemical entities and combinations of the present chemical entitieswith various other chemical entities and with various penetrationpromoting devices.

BACKGROUND OF THE INVENTION

Local anesthetics are membrane stabilizing agents that block nerveconduction by decreasing or preventing permeability of the cell membraneto sodium ions produced during depolarization of the membrane. Whenadministered to specific nerve pathways, effects such as analgesia (lossof pain sensation) and paralysis (loss of muscle power) can be achieved.Amide-type anesthetics, such as lidocaine, prilocaine, mepivacaine andbupivacaine, contain an “amide linker” and have been shown to possesslocal anesthetic effects and are widely used for infiltration anesthesiaand for inducing nerve blocks. These compounds have limited use asdermal anesthetics since they have to be given in high concentrations,which increase the risk of tissue irritation and tissue damage. Othercompounds, such as tetracaine and procaine, are better suited for dermalanesthesia since they may better penetrate through tissue. However,tetracaine and procaine contain an “ester linker” and are known to causetissue irritation and to be unstable in the human body where practicallyall tissues contain esterases.

Aberg, et al. developed a set of compounds known as “aminoindanepiperidine compounds” for use as dermal and topical anesthetics thatshowed less tissue toxicity than ester-type local anesthetics. Theseaminoindane piperidine compounds, described in U.S. Pat. No. 6,413,987,the disclosure of which is hereby incorporated by reference, contain anamine linker group attached to the piperidine ring at the para, meta orortho position. These compounds are described as potent membranestabilizing agents with a prolonged anesthetic effect having a shortonset of action and readily penetratable into various tissues, e.g.,ocular tissue, mucosal tissue, rectal tissue and skin. One particularcompound that has been identified as particularly useful for dermalanesthesia and as producing little, if any, tissue toxicity is2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine [RS-LAC-34, racemicmixture].

In addition to the aminoindane piperidine compounds described in U.S.Pat. No. 6,413,987, additional aminoindane compounds are described in anumber of patents to Vanhoof, et al. (GB 1 321 424; U.S. Pat. No.3,923,813; U.S. Pat. No. 3,923,815; and U.S. Pat. No. 3,923,887). Theseaminoindanes, having an N-substituted piperidine ring, are described asantiarrhythmic compounds that also possess local anesthetic activity.

Toxicity studies comparing aminoindanes described by Vanhoof et al. andthe aminoindanes described by Aberg, et al. show that the N-substitutedpiperidine compounds of Vanhoof have no clinical usefulness as local ordermal anesthetics as these tertiary amines were found to cause tissuetoxicity. In contrast, the aminoindanes described by Aberg et al. werefound to be useful as local or dermal anesthetics.

While various local anesthetic compounds are known in the art, thereremains a need to provide for additional local anesthetic compounds thatreadily penetrate tissue without causing tissue toxicity, and forproviding local anesthetic compounds having a long duration of action.The above needs are met by the compounds described herein.

The present invention describes the S-isomer of compounds of Formula Ias described above. Specifically, the present invention describesS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine [S-LAC-34] the freebase, polymorphs, metabolites, derivatives, pharmaceutically acceptablesalts and mixtures thereof. S-LAC-34 refers to the S-enantiomer of theracemic compound RS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine.S-LAC-34 has the formula:

S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine [S-LAC-34]

Isomerism refers to the phenomenon where two compounds have identicalchemical structure, i.e., have the same order of attachment ofindividual atoms, but differ in spatial configuration of the atoms. Thespatial configuration of the atoms is usually determined by the use ofX-ray crystallography or by known stereo specific synthetictransformations. Once known, the spatial configuration is labeled withsymbols “R” or “S” according to the Cahn, Ingold, and Prelog system.Under the system, the atoms or groups surrounding an asymmetric centerare given priorities according to atomic number and various sequenceconsiderations. Then, the molecule is rotated so that the group withlowest priority is away from the viewer. Finally, it is observed whetherthe atoms in the descending order of priority form the clockwise orcounterclockwise motion. If the motion is clockwise, the configurationis labeled “R” and the compound is referred to as an S-isomer. If themotion is counterclockwise, the configuration is labeled “S” and thecompound is referred as an S-isomer.

As actions of pharmaceutical compounds may be the result of interactingwith biological receptors, and the biological receptors may be stereoselective, R and S isomers may possess different pharmacologicalactivities and effects upon administration to a subject. For example,one of the isomers may be more potent (require a smaller dose to reach adesired effect). Similarly, one of the isomers may have a faster onsetof action and/or a longer duration of action. Further, one of theisomers may have lower incidents of adverse effects.

The racemic compound, RS-LAC-34, has been shown to be an active localanesthetic compound, particularly useful for dermal anesthesia (U.S.Pat. No. 6,413,987). It has now been found that S-LAC-34 differssignificantly from the racemate and R-LAC-34. S-LAC-34 has a longerduration of action than both the racemate and the S-isomer. Furthermore,while suitable for use as a local anesthetic, the S-isomer expressesanalgesic activity and may therefore be effective for treating pain. TheS-isomer also has low dermal toxicity and may be combined with avasoconstrictor to obtain an even more prolonged duration of localanesthesia.

OBJECT AND SUMMARY OF THE INVENTION

It is an object of the invention to provide for the S-isomer ofcompounds of Formula I.

It is another object of the invention to provide for pharmaceuticalformulations containing the S-isomer of compounds of Formula I, the freebase, polymorphs, derivatives, metabolites, pharmaceutically acceptablesalts and mixtures thereof.

It is a further object of the present invention to provide compositionsand methods for providing local anesthesia by administering to adiscrete site in a patient a therapeutically effective amount of theS-isomer of Formula I for inducing anesthesia.

It is another object of the present invention to provide compositionsand methods for providing pain relief in a patient by administering atherapeutically effective amount of the S-isomer of compounds of FormulaI to a discrete site in a patient for the treatment of acute or chronicpain, nociceptive and neuropathic pain, pre- and post-operative pain,cancer pain, pain associated with neurotransmitter dysregulationsyndromes and orthopedic pain.

It is another object of the invention to provide compositions andmethods for improving sleep behavior in a patient by administering atherapeutically effective amount of the S-isomer of compounds of FormulaI to a discrete site in a patient in need of pain relief, therebyalleviating the pain and improving the sleep of the patient.

It is an object of the present invention to provide the S-isomer of2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34).

It is another object of the present invention to provide pharmaceuticalformulations containing S-LAC-34, the free base, polymorphs,derivatives, metabolites, pharmaceutically acceptable salt and mixturesthereof.

It is a further object of the present invention to provide compositionsand methods for providing local anesthesia by administering to adiscrete site in a patient a therapeutically effective amount ofS-LAC-34 for inducing anesthesia.

It is another object of the present invention to provide compositionsand methods for providing pain relief in a patient by administering atherapeutically effective amount of S-LAC-34 to a discrete site in apatient for the treatment of acute or chronic pain, nociceptive andneuropathic pain, pre-and post-operative pain, cancer pain, painassociated with neurotransmitter dysregulation syndromes and orthopedicpain.

It is another object of the invention to provide compositions andmethods for improving sleep behavior in a patient by administering atherapeutically effective amount of S-LAC-34 to a discrete site in apatient in need of pain relief, thereby alleviating the pain andimproving the sleep of the patient.

It is a further object of present invention to provide processes for thepreparation of S-LAC-34.

In accordance with the above objects and others, in certain embodimentsof the present invention there is provided the S-isomer of the formula:

or a pharmaceutically acceptable salt, base, or mixture thereof, whereinn is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or anoxygen atom, the (CH₂)_(n) group having a straight or branched chain, Brepresents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms ora group of the formula

in which R₃ and R₄ may independently be selected from the groupconsisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radicalcontaining 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen,A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenylradical substituted by at least one substituent in the ortho, metaand/or para position, and R₁ represents a hydrogen, or a lower alkyl orhydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleusis attached at the 2-, 3-, or 4-position, wherein the compound is usefulfor inducing anesthesia and analgesia in a patient in need thereof, thecompound having a long duration of action when administered to apatient.

In accordance with the above objects and others, in certain embodimentsof the present invention there is also provided S-LAC-34 having theformula:

or a free base, pharmaceutically acceptable salt, polymorph or mixturethereof, wherein the compound is useful for inducing anesthesia andanalgesia in a patient in need thereof, the compound having a longduration of action when administered to a patient.

In certain embodiments, there is provided a substantially pure S-isomerof the compounds described herein. The compounds contain substantiallypure S-isomer when the compound is 95% or more S-isomer. In otherembodiments, the compounds contain 97% or more S-isomer. In yet anotherembodiment, the compounds contain 99% or more S-isomer.

In certain embodiments, a substantially pureS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine is provided.Substantially pure S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidinecontains 95% or moreS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine. In otherembodiments, substantially pureS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine contains 97% ormore S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine. In yetanother embodiment, substantially pureS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine contains 99% ormore S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine.

In certain embodiments, there is provided a pharmaceutical formulationfor providing anesthesia and analgesia in a patient in need thereofcomprising a therapeutically effective amount of a compound of formula 1and a pharmaceutically acceptable excipient.

In other embodiments, the pharmaceutical formulation containssubstantially pure S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine(S-LAC-34) and a pharmaceutically acceptable excipient.

The S-isomer of the compounds of the present invention, e.g., S-LAC-34,may be useful for providing local anesthesia to a patient in needthereof. In particular, it may be useful for providing topicalanesthesia, dermal anesthesia, ocular anesthesia, mucosal anesthesia,intravenous regional anesthesia, infiltration anesthesia, field blockanesthesia, and nerve block anesthesia. Infiltration anesthesia andnerve blocks include epidural anesthesia, spinal anesthesia, dentalanesthesia and peripheral nerve blocks. Dermal anesthesia comprisesanesthesia, for example, for the removal of lentigens, for skin graftsor for sunburns. Topical mucosal anesthesia comprises local anesthesiaby topical application or by topical injections of any accessible mucousmembrane, such as for example those of the eye, mouth, theear-nose-throat, the rectal area and the uro-genital tract.

Of particular interest is the use of the compounds in dentistry, whereinfiltration anesthesia of the lower jaw may be achieved because of theoutstanding ability of the compound to penetrate biological tissues;presently infiltration anesthesia is used for the upper jaw, whilemandibular nerve blocks have to be used for the lower jaw, where thebone structure is of high density.

When used as a topical anesthetic to eliminate pain from hemorrhoids,the long duration of the relief may be of special importance, as is thelack of unwanted effects on wound healing.

The compounds herein may be of particular importance for use in dermalanesthesia, wherein a longer duration of dermal anesthesia is sought.

In certain embodiments, there is provided a method of inducinganesthesia in a patient in need thereof, comprising administering to adiscrete site in a patient in need thereof an anesthetic inducing amountof a substantially pure S-isomer of a compound of formula I. In certainembodiments, the substantially pure isomer isS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34), whereinthe S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34)provides an immediate anesthetic effect when administered to thediscrete site.

The compounds described herein may also be useful for providinganalgesia to a patient in need thereof for relieving pain such as acuteor chronic pain, nociceptive pain (pain transmitted across intactneuronal pathways), neuropathic pain (pain caused by damage to neuralstructures), pain from nerve injury (neuromas and neuromas incontinuity), pain from neuralgia (pain originating from disease and/orinflammation of nerves), pain from myalgias (pain originating fromdisease and/or inflammation of muscle), pain associated with painfultrigger points, pain from tumors in soft tissues, pain associated withneurotransmitter-dysregulation syndromes (disruptions inquantity/quality of neurotransmitter molecules associated with signaltransmission in normal nerves) and pain associated with orthopedicdisorders such as conditions of the foot, knee, hip, spine, shoulders,elbow, hand, head and neck.

In certain embodiments, there is provided a method of providinganalgesia or alleviating pain in a patient in need thereof, comprisingadministering to a discrete site in a patient in need thereof ananalgesic effective amount of a substantially pure isomer of a compoundof Formula I. In certain embodiments, the substantially pure isomer isS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34), whereinthe S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34)provides a longer duration of analgesic effect when administered to thediscrete site.

In other embodiments, the S-isomers of the compounds described herein,may be useful for improving sleep behavior (patterns), whereby treatmentof the underlying pain or painful condition allows a patient to haveimproved sleep.

In certain embodiments, there is provided a method of improving sleep ina patient in need thereof, comprising administering to a discrete sitein a patient in need thereof an analgesic effective amount of asubstantially pure S-isomer of Formula I. In another embodiment, thesubstantially pure S-isomer isS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34), whereinthe S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34)alleviates pain experienced by the patient and provides for improvedsleep resulting from the alleviation of pain.

In other embodiments, S-isomer of the compounds of the invention may beuseful for treating various other conditions such as hemorrhoids,arrhythmias, convulsions, hiccups and can be used to inhibit sodium andpotassium ion fluxes over cell membranes in the body.

The pharmacological effects of the S-isomer of the compounds describedherein may provide a longer duration of action, thus making the S-isomera pharmaceutically effective treatment for inducing a prolongedanesthetic effect and/or providing prolonged analgesia in an acutesetting. The long duration of action may also make the compounds usefulto treat chronic conditions such that a single dose may be administeredat the onset of symptoms and provide a prolonged pharmacological effect.

In other embodiments, there is provided a process for preparing asubstantially pure S-isomer of the compounds of formula I, wherein thechirality of the S-isomer is established from the beginning.

In certain embodiments, the substantially pure isomer isS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34) which isprepared by: a) sequentially converting: i) an N-protected L-pipecolicacid to a corresponding diazomethyl ketone; ii) the diazomethyl ketoneto a methyl ester; iii) the methyl ester to a primary alcohol; and iv)the primary alcohol to an alkyl halide; b) reacting the resultingS-alkyl halide with 2-(phenylamino)indane; and c) removing anN-protecting group to obtainS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34).

In order that the invention described herein may be more fullyunderstood, the following definitions are provided for the purposes ofthis disclosure:

“Patient” refers to animals, preferably mammals, more preferably humans.The term “patient” includes adults and children, and includes men andwomen. Children include neonates, infants, and adolescents.

The term “environmental fluid” described herein shall mean anyenvironmental or biological fluid. For example, certain biologicalfluids include, but are not limited to, gastrointestinal fluid, saliva,blood, lymph fluid, cerebrospinal fluid, ocular fluid, intra-articularfluid and any other fluid of a patient.

“Acute pain” shall mean any pain that presents with a rapid onsetfollowed by a short, severe course, e.g., headache, pain associated withcancer, fractures, strains, sprains, and dislocations of bones, joints,ligaments and tendons.

“Chronic pain” shall mean pain that lasts for a long period of time oris marked by frequent recurrence, e.g., pain associated with terminalillnesses, arthritis, autoimmune diseases; or neuropathic pain caused bydegenerative diseases such as diabetes mellitus or spinal degeneration,or resulting from neural remodeling following traumatic injury orsurgery.

As used herein, the term “local anesthetic” means any drug or mixture ofdrugs that provides local numbness and/or analgesia.

The term “prodrug” as used herein means an inactive precursor(s) of thecompounds described herein that may be converted into the active form ofthe compound(s) in the body by normal metabolic processes.

The term “oral” administration means by mouth and gastrointestinal tractby mouth.

The term “parenteral” means intravenous, intrarterial, intracardiac,intraspinal, intraosseous, intrarticular, intrasynovial, intracutaneous,subcutaneous, and intramuscular by injection, implantation orinfiltration.

The term “injection” shall mean administration to a discrete sitethrough the skin or into tissue of a human or animal.

The term “implantation” shall mean administration to a discrete site byembedding the dose of compound into the skin, tissue, muscles, tendons,joints, or other body parts of a human or animal.

The term “infiltration” shall mean administration into a discreteinjection site, or surgical site or open wound.

The term “topical anesthesia” is in this document defined as localanesthesia of mucosal membranes, such as for examples those of the eye,the ear, the mouth, the nose, the rectal area and the urogenital tract.

The term “dermal anesthesia” is in this document defined as localanesthesia of the skin.

“Infiltration anesthesia” and “nerve blocks” of afferent or efferentnerves are in this document called “local anesthesia”.

The term “ocular” administration means conjunctival, corneal, andintraocular administration.

By co-administration it is meant either the administration of a singlecomposition containing both the compound and an additionaltherapeutically effective agent(s), e.g., local anesthetic or phenol, orthe administration of the compound and the additional therapeuticallyeffective agent(s) as separate compositions within short enough timeperiods that the effective result is equivalent to that obtained whenboth compounds are administered as a single composition.

The term “substantially pure isomer” means containing 95% or more of thetarget isomer and no more than 5% other impurities, which may includeother isomers of the desired compound, e.g., S-isomer.

The term “capsaicinoid” as used herein means capsaicin, capsaicin USPand purified capsaicin, capsaicin analogues and derivatives thereof(collectively referred to as capsaicinoids in this specification andappended claims) that act at the same pharmacologic sites, e.g., VR1, ascapsaicin, unless otherwise specified.

The term “long duration of action” means a prolonged pharmacologicaleffect, e.g., anesthesia or analgesia, upon administration of thecompounds to a discrete site. For purposes of the present invention,“prolonged duration of action” is further defined as producing apharmacological effect that is longer in comparison to lidocaine, theracemate of LAC-34 and the S-Isomer of LAC-34 when administered at thesame concentration.

The term “therapeutically effective amount” means an amount ofcompound/active agent, whereby a desired effect is obtained, e.g.,induction of anesthesia or attenuation/relief from pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows dermal anesthetic effects of the enantiomers of LAC-34. Theonset of dermal anesthetic activity was significantly shorter forR-LAC-34 (score 3.5 after 30 min application) than for S-LAC-34 (score2.6).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are substantially pure S-isomersof the general formula I:

or a pharmaceutically acceptable salt, base, or mixture thereof, whereinn is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or anoxygen atom, the (CH₂)_(n) group having a straight or branched chain, Brepresents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms ora group of the formula

in which R₃ and R₄ may independently be selected from the groupconsisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radicalcontaining 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen,A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenylradical substituted by at least one substituent in the ortho, metaand/or para position, and R₁ represents a hydrogen, or a lower alkyl orhydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleusis attached at the 2-, 3-, or 4-position.

In certain preferred embodiments, the compound is an S-isomer of2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine [S-LAC-34] having thefollowing formula:

S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine [S-LAC-34]

The compounds described herein may be the free base, a polymorph(s), ametabolite, a derivative(s), a pharmaceutically acceptable salt ormixtures thereof.

The compounds have local and dermal anesthetic activities, characterizedby a longer duration of activity, e.g., time for dermal anestheticactivity, thereby making it possible to obtain long duration without theuse of a vasoconstrictor, such as epinephrine, in the local anestheticformulation. This property distinguishes the S-isomer apart from otherknown local anesthetic compounds—including the racemic mixture andR-isomer, e.g., R-LAC-34, which has a shorter onset of action and ashorter duration of action—and opens the possibility of using thisoptically active local anesthetic agent in ways that have not beenpossible for prior generations of local anesthetics. Comparisons of thetwo enantiomers of RS-LAC-34 show that S-LAC-34 demonstrates a longerduration of anesthesia than the racemic mixture or the R-isomer(R-LAC-34), which indicates unique biological effects. The compoundS-LAC-34 has low dermal toxicity and can be combined with avasoconstrictor to obtain an even more prolonged duration of localanesthesia. These unique properties are believed to be present with theS-isomers of the compounds of Formula I as well.

Administration of the Compounds

All compositions containing the compounds of the invention may bemanufactured in different dosage units, suitable for administrationunder specific circumstances.

Suitable methods for administration of may include, but are not limitedto, oral, sublingual, parenteral, rectal, urogenital, ocular, andtopical administration. In clinical use, the compounds of the inventionmay be administered in combination with a pharmaceutically acceptableexcipient (carrier), either as the free base, as a pharmaceuticallyacceptable, non-toxic acid addition salt.

The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to:i) metal salts such as aluminum, cesium, lithium, potassium, sodium,zinc salts, and the like; ii) alkaline earth metals salts such ascalcium, magnesium salts, and the like; iii) organic amine salts such asdicyclohexylamine, diethylamine, ethanolamine, pyridine, picoline,triethylamine, triethanolamine, and N,N′-dibenzylethylenediamine salts,and the like; iv) inorganic acid salts such as acetate, bicarbonate,hydrochloride (mono-and dihydrochloride), hydrobromide, hydroiodide,mesylate, besylate, lactate, nitrate, sulfate, bisulfate, acidphosphate, phosphate salts, sulfonate, and the like; v) organic acidsalts such as acetate, adipate, alginate, aspartate, ascorbate, citrate,benzate, besylate, butyrate salt, bitartrate, camphorate, camphorsulfonate, digluconate, formate, fumarate, glutarate, gluconate,glucoronate, gentisinate, glycerophosphate, hemisulfate, heptanoate,hexanoate, lactate, p-hydroxybenzoate, p-methoxybenzoate,hydoxynaptoicoate, isonicotinate, pantothenate, oxalate, palmitoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, salicylate, succinate, undecanoate, pamoate, saccharate,trifluoroacetate, thiocyanate, maleate, tartrate salts, and the like;sulfonates salts such as methanesulfonate, ethanesulfonate,2-hydroxyehansulfonate (isothionate), 2-naphthalene sulfonate,benzenesulfonate, bisulfate, toluenesulfonate (includingp-toluenesulfonate) salts, and the like; vi) amino acid salts such asarginate, asparginate, glutamate salts and the like.

In certain embodiments, the compounds may be suitable for parenteraladministration. The compounds may be administered parenterally byintravenous, intraarterial, intracardiac, intraspinsal, intraosseous,intraarticular, intrasynovial, subcutaneous or intramuscular injection,implantation, infiltration or infusion.

In certain preferred embodiments, the compounds may be administeredparenterally via intradermal injection.

When S-LAC-34 is administered parenterally, in certain embodiments, thecompound may be administered alone or together with a pharmaceuticallyacceptable and physiological acceptable excipients, e.g., diluent, forparenteral administration. Solutions for parenteral administration(e.g., injection or infusion) may be prepared as aqueous solutions of awater soluble, pharmaceutically acceptable salt of the active compound,such as for example the dihydrochloride salt in a concentration from0.1% to 3.0%.

Suitable diluents for parenteral administration include, but are notlimited to: aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and anycombinations or mixtures thereof. Examples of aqueous vehiclespreferably include Sodium Chloride Injection, Bacteriostatic SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Bacteriostatic Sterile Water Injection,Dextrose Lactated Ringers Injection and any combinations or mixturesthereof. Nonaqueous parenteral vehicles preferably include fixed oils ofvegetable origin, cottonseed oil, corn oil, sesame oil, peanut oil andany combinations or mixtures thereof. Antimicrobial agents inbacteriostatic or fungistatic concentrations preferably include phenols,cresols, mercurials, benzyl alcohol, chlorobutanol, ethyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloridebenzethonium chloride and mixtures thereof. Isotonic agents preferablyinclude sodium chloride, dextrose and any combinations or mixturesthereof. Buffers preferably include acetate, phosphate, citrate and anycombinations or mixtures thereof. Antioxidants preferably includeascorbic acid, sodium bisulfate and any combinations or mixturesthereof. Suspending and dispersing agents preferably include sodiumcarboxymethylcelluose, hydroxypropyl methylcellulose,polyvinylpyrrolidone and any combinations or mixtures thereof.Emulsifying agents preferably include Polysorbate 80 (Tween 80).Sequestering or chelating agents of metal ions preferably includeethylenediaminetetraacetic acid. Additional pharmaceutically acceptablevehicles also preferably include ethyl alcohol, polyethylene glycol,glycerin, propylene carbonate and propylene glycol for water misciblevehicles and sodium hydroxide, hydrochloric acid, citric acid or lacticacid for pH adjustment and any combinations or mixtures thereof.

Depending on the pharmaceutically acceptable vehicle chosen, thecompounds may be administered as an aqueous solution or suspension forinjection, implantation or infiltration. Injections are separated intofive distinct types, generally classified as (i) medicaments orsolutions or emulsions suitable for injection; (ii) dry solids or liquidconcentrates containing no buffers, diluents, or other added substances,and which upon the addition of suitable vehicles, yield solutionsconforming in all aspects to the requirements for injections; (iii)preparations as described in (ii) except that they contain one or morebuffers, diluents or other added substances; (iv) solids which aresuspended in a suitable fluid medium and which are not to be injectedintravenously or into the spinal canal; and (v) dry solids, which uponthe addition of suitable vehicles, yield preparations conforming in allrespects to the requirements of Sterile Suspensions (see: H. C. Ansel,Introduction to Pharmaceutical Dosage Forms, 4th Edit., 1985, pg. 238).

In certain other embodiments, a surfactant can preferably be combinedwith one or more of the pharmaceutically acceptable vehicles previouslydescribed herein so that the surfactant or buffering agent prevents theinitial stinging or burning discomfort that may be associated withadministration of the compounds described herein.

Suitable surfactants include, but are not limited to, sodium stearylfumarate, diethanolamine cetyl sulfate, polyethylene glycol,isostearate, polyethoxylated castor oil, benzalkonium chloride, nonoxyl10, octoxynol 9, polyoxyethylene sorbitan fatty acids (polysorbate 20,40, 60 and 80), sodium lauryl sulfate, sorbitan esters (sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitantristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate,sorbitan stearate, sorbitan dioleate, sorbitan sesqui-isostearate,sorbitan sesquistearate, sorbitan tri-isostearate),-lecithinpharmaceutical acceptable salts thereof and combinations thereof. Whenone or more surfactants are utilized in the formulations of theinvention, they may be combined, e.g., with a pharmaceuticallyacceptable vehicle and may be present in the final formulation, e.g., inan amount ranging from about 0.1% to about 20%, more preferably fromabout 0.5% to about 10%.

Buffering agents may also be used to provide drug stability; to controlthe therapeutic activity of the drug substance (Ansel, Howard C.,“Introduction to Pharmaceutical Dosage Forms,” 4.sup.th Ed., 1985);and/or to prevent the initial stinging or burning discomfort that mayalso be associated with administration of the compounds describedherein. Suitable buffers include, but are not limited to sodiumbicarbonate, sodium citrate, citric acid, sodium phosphate,pharmaceutically acceptable salts thereof and combinations thereof. Whenone or more buffers are utilized in the formulations of the invention,they may be combined, e.g., with a pharmaceutically acceptable vehicleand may be present in the final formulation, e.g., in an amount rangingfrom about 0.1% to about 20%, more preferably from about 0.5% to about10%.

In certain preferred embodiments, the pharmaceutical vehicle utilized todeliver the compounds by injection may comprise about 20% PEG 300, about10 mM histidine and about 5% sucrose in water for injection.

The percentage of the compounds described herein contained in apharmaceutically acceptable formulation for parenteral administrationmay vary. In certain embodiments, the compounds may be present in aformulation in an amount to provide for about 0.001% to about 25% byweight of the compound. In other embodiments, the compounds may bepresent in a formulation in an amount to provide for a about 0.05% toabout 10% by weight of the compound. In yet another embodiment, thecompounds may be present in a formulation in an amount to provide for a0.1% to about 5% by weight of the compound. In other embodiments, theamount of compound may range from about 0.1% to about 3% by weight forinjections or from about 0.05% to 3% by weight for infusions (e.g., forepidural, spinal or regional anesthesia). In yet another embodiment, thecompounds may be present in an amount from about 0.1% to about 10% byweight for preparations for dermal anesthesia.

Formulations for parenteral administration may contain the compound as afree base or water-soluble salt, such as for example thedi-hydrochloride salt.

If parenteral administration is not viable or another form ofadministration is desired, the compounds may be administered topicallyor transdermally by known methods. In certain embodiments, the compoundsmay be administered as a cream, ointment, emollient, paste, gel,solution, suspension, liposome, aerosol or spray. In certainembodiments, the compounds may be administered in a transdermal patch.In other embodiments, an occlusive dressing may be placed over the areawhere the compound is topically applied.

Topical administration includes, but is not limited to, epicutaneous,transdermal, conjunctival, intraocular, intranasal, intrarespiratory,aural, mucosal, rectal, vaginal, and urethral administration.

While the various salt forms of the compounds are useful in dermalanesthesia, dermal formulations containing the free base may bepreferred.

The topical formulations and/or transdermal therapeutic systems of thepresent invention may include at least one excipient such as apenetration enhancer, anti-oxidant, stabilizer, carrier, or vehicle.

In certain embodiments of the present invention, wherein the topicalformulation further includes a penetration enhancer composition, theamount of enhancer composition present in the formulation will depend ona number of factors, e.g., the strength of the particular enhancercomposition, the desired increase in skin permeability, and the amountof drug which is necessary to deliver.

Suitable enhancers include, but are not limited to, dimethylsulfoxide(DMSO), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C₁₀ MSO),polyethylene glycol monolaurate (PEGML), propylene glycol (PG), PGML,glycerol monolaurate (GML), polyoxyethylene fatty acid esters, lecithin,the 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAzone® from Whitby Research Incorporated, Richmond, Va.), alcohols, andthe like. The permeation enhancer may also be a vegetable oil asdescribed in U.S. Pat. No. 5,229,130 to Sharma. Such oils include, forexample, safflower oil, cotton seed oil and corn oil.

Additional enhancers for use in conjunction with the present inventionare lipophilic compounds having the formula [RCOO]_(n) R′, wherein n is1 or 2 and R is C₁-C₁₆ alkyl optionally substituted with 1 or 2 hydroxylgroups, and R′ is hydrogen or C₁-C₁₆ alkyl optionally substituted with 1or 2 hydroxyl groups. Within this group, a first subset of compounds arerepresented by the formula [CH₃ (CH₂)_(m) COO]_(n) R′ in which m is aninteger in the range of 8 to 16, n is 1 or 2, and R′ is a lower alkyl(C₁-C₃) residue that is either unsubstituted or substituted with one ortwo hydroxyl groups. Preferred enhancers within this group include anester which is a lower alkyl (C₁-C₃) laurate (i.e., m is 10 and n is 1)such as “PGML”. It will be appreciated by those skilled in the art thatthe commercially available material sold as “PGML” is typically althoughnot necessarily a mixture of propylene glycol monolaurate itself,propylene glycol dilaurate, and either propylene glycol, methyl laurate,or both. Thus, the terms “PGML” or “propylene glycol monolaurate” asused herein are intended to encompass both the pure compound as well asthe mixture that is typically obtained commercially. Also within thisgroup is a second subset of compounds, namely, esters of fatty alcoholsrepresented by the formula CH₃ (CH₂)_(m)-O—CO—CHR₁ R₂, in which R₁ andR₂ are independently hydrogen, hydroxyl, or lower alkyl (C₁-C₃), and mis as above. Particularly preferred enhancers within this group arelauryl lactate and myristyl lactate. In addition, a third subset ofcompounds within this group are analogous fatty acids, i.e., acidshaving the structural formula CH₃ (CH₂)_(m) COOH where m is as above. Aparticularly preferred acid is lauric acid.

Other enhancer compositions are wherein a lipophilic compound as justdescribed, particularly PGML is combined with a hydrophilic compound,such as a C₂-C₆ alkanediol. One preferred hydrophilic enhancer withinthis group is 1,3-butanediol. Such enhancer compositions are describedin detail in PCT Publication No. WO 95/05137, published Feb. 23, 1995,herein incorporated by reference. Another hydrophilic enhancer that maybe included in these compositions is an ether selected from the groupconsisting of diethylene glycol monoethyl ether (Transcutol®) anddiethylene glycol monomethyl ether. Such enhancer compositions aredescribed in detail in U.S. Pat. Nos. 5,053,227 and 5,059,426 to Chianget al., the disclosures of which are herein incorporated by reference.

Other enhancer compositions may include mixture or combinations of anyof the aforementioned enhancers, and the like.

In certain embodiments the topical formulation may include at least onewater-insoluble, pharmacologically approved, cellulose, such as alkylcellulose or hydroxyalkyl cellulose, and the like. Alkyl cellulose orhydroxyalkyl cellulose polymers for use in this invention include ethylcellulose, propyl cellulose, butyl cellulose, cellulose acetate,hydroxypropyl cellulose, hydroxybutyl cellulose, and ethylhydroxyethylcellulose, alone or in combination. In addition, a plasticizer or across linking agent may be used to modify the polymer's characteristics.For example, esters such as dibutyl or diethyl phthalate, amides such asdiethyldiphenyl urea, vegetable oils, fatty acids and alcohols such asoleic acid and myristyl may be used in combination with the cellulosederivative.

In certain embodiments, the topical formulation may further includehydrocarbons such as liquid paraffin, vaseline, solid paraffin,microcrystalline wax, etc.; higher aliphatic alcohols such as cetylalcohol, hexadecyl, alcohol, stearyl alcohol, oleyl alcohol, etc.;esters of higher fatty acids with higher alcohols such as beeswax, etc.;esters of higher fatty acids with lower alcohols such as isopropylmyristate, isopropyl palmitate, etc.; vegetable oils, modified vegetableoils, hydrous lanolin and its derivative, squalene, squalane; higherfatty acids such as palmitic acid, stearic acid, etc. and the like.

In certain embodiments, the topical formulation may further includeemulsifiers and dispersing agents which include, for example, anionic,cationic and nonionic surfactants. Nonionic surfactants are preferredbecause of their low levels of irritation to skin. Typical of nonionicsurfactants are fatty acid monoglycerides such as glyceryl monostearate,etc.; sorbitan fatty acid esters such as sorbitan monolaurate, etc.;sucrose fatty acid esters; polyoxyethylene fatty acid esters such aspolyoxyethylene stearate, etc.; and polyoxyethylene higher alcoholethers such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether,etc.

In certain embodiments of the present invention, the topical formulationmay include a gelling agent such as methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, carbomer, and thelike.

The topical formulation may further include one or more antimicrobialagents, preservatives, buffers, stabilizers, surfactants oranti-oxidants.

Examples of preservatives that may be used in a formulation according tothe present invention include, but are not limited to, bacteriostaticcompounds and other preservatives suitable for topical administrationincluding various alcohols, sorbic acid and salts and derivativesthereof, ethylenediamine, monothioglycerol, and thimerosal.

Examples of stabilizers that may be present in a formulation accordingto the present invention include pH buffers suitable for topicaladministration, complexing agents, chelating agents and the like.

Examples of anti-oxidants that may be used in a formulation according tothe present invention include ascorbic acid and its derivatives, e.g.,ascorbyl palmitate, as well as butylated hydroxyanisole, butylatedhydroxytoluene, sodium bisulfite, sodium metabisulfite, and others.

Other excipients that may be included in the drug formulation includecarriers, thickening agents (e.g. carboxypoly-methylene), pH-adjustingagents (e.g. sodium hydroxide), preservatives, tackifiers, pigments,dyes, and other additives that do not adversely affect the mechanical oradhesive properties of the formulation. “Carriers” or “vehicles” as usedherein refer to carrier materials suitable for transdermal drugadministration, and include any such materials known in the art, e.g.,any liquid, gel, emulsion, solvent, liquid diluent, solubilizer, or thelike, which is nontoxic and which does not interact with othercomponents of the composition in a deleterious manner. The term“carrier” or “vehicle” as used herein may also refer to stabilizers,crystallization inhibitors, dispersing agents or other types ofadditives useful for facilitating transdermal drug delivery. It will beappreciated that compounds classified as “vehicles” or “carriers” maysometimes act as permeation enhancers, and vice versa, and, accordingly,these two classes of chemical compounds or compositions may sometimesoverlap.

Carrier materials suitable for use in the instant compositions includethose well-known for use in the cosmetic and medical arts as bases forointments, lotions, salves, aerosols, suppositories and the like.Suitable carriers include, for example, water, liquid alcohols, liquidglycols, liquid polyalkylene glycols, liquid esters, liquid amides,liquid protein hydrolysates, liquid alkylated protein hydrolysates,liquid lanolin and lanolin derivatives, and like materials commonlyemployed in cosmetic and medicinal compositions. Other suitable carriersherein include for example alcohols, including both monohydric andpolyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol,2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol,mannitol, and propylene glycol; ethers such as diethyl or dipropylether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxeshaving molecular weight ranging from 200 to 20,000); polyoxyethyleneglycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

In certain embodiments, excipients such as mineral oil andcapric/caprylic triglycerides may be used as the oil phase foremollients or emulsions.

The combination of excipients provides means of delivering the drug fromsupersaturated compositions through skin where the penetration barriersare decreased, while the formulations also are repairing barrier damage,protecting the skin, and hydrating the skin.

The topical and/or transdermal composition may contain one or moreactive compounds and the compounds may be prepared as bases or salts tofacilitate dermal penetration.

The topical or transdermal formulations of the present invention may beformulated in a manner such that the percentage of compound contained inthe formulation ranges from about 0.001% to about 25% by weight. Incertain embodiments, the compound may be present in a formulation in anamount from about 0.01% to about 10% by weight. In yet anotherembodiment, the compound may be present in a formulation in an amountfrom about 0.1% to about 5% by weight. In yet another embodiment, thecompound may be present in an amount from about 0.1% to about 10% byweight for preparations for topical mucosal anesthesia or from about0.05% to about 2.5% by weight in preparations for use on mucousmembranes.

The compounds of the present invention may also be formulated into asuitable ophthalmic preparation. In certain embodiments, the ophthalmicpreparation may contain additional active agents such as, but notlimited to, an antibiotic, a vasoconstrictor, a vasodilator, aglucocorticosteroid, an antiseptic and/or bacteriostatic agent.

The compounds may be formulated into suitable dosage forms for rectal orvaginal administration. Dosage units for rectal or vaginaladministration may be prepared in the form of ointments orsuppositories, which may contain the active substance in a mixture witha neutral fat base, or they may be prepared in the form ofgelatin-rectal or vaginal capsules that contain the compound in amixture with for example a vegetable oil or paraffin oil. Ointments,suppositories or creams containing the compound may be useful for thetreatment of hemorrhoids. In certain embodiments, co-administration ofthe S-LAC-34 with a vasoconstrictor may be particularly useful for thetreatment of hemorrhoids.

Delivery systems can also be used to administer the compounds of thepresent invention. The delivery systems may produce modality-specificblockade, as reported by Schneider, et al., Anesthesiology, 74:270-281(1991), or possess physical-chemical attributes that make them moreuseful for sustained release then for single injection blockade, asreported by Masters, et al., Soc. Neurosci. Abstr., 18:200 (1992), theteachings of which are incorporated herein. An example of a deliverysystem includes microspheres wherein the compound may be incorporatedinto a polymer matrix in a percent loading of 0.1% to 90% by weight,preferably 5% to 75% by weight. It is possible to tailor a system todeliver a specified loading and subsequent maintenance dose bymanipulating the percent of the compound incorporated in the polymer andthe shape of the matrix, in addition to the form of local anesthetic(free base versus salt) and the method of production. The amount ofcompound released per day increases proportionately with the percentageof compound incorporated into the matrix (for example, from 5 to 10 to20%).

The delivery systems are most preferably formed of a syntheticbiodegradable polymer, although other materials may also be used toformulate the delivery systems, including proteins, polysaccharides, andnon-biodegradable synthetic polymers. It is most preferable that thepolymer degrade in vivo over a period of less than a year, with at least50% of the polymer degrading within six months or less. Even morepreferably, the polymer will degrade significantly within a month, withat least 50% of the polymer degrading into non-toxic residues which areremoved by the body, and 100% of the compound being released within atwo week period. Polymers should also preferably degrade by hydrolysisby surface erosion, rather than by bulk erosion, so that release is notonly sustained but also linear. Polymers which meet this criteriainclude some of the polyanhydrides, poly(hydroxy acids) such asco-polymers of lactic acid and glycolic acid wherein the weight ratio oflactic acid to glycolic acid is no more than 4:1 (i.e., 80% or lesslactic acid to 20% or more glycolic acid by weight), and polyorthoesterscontaining a catalyst or degradation enhancing compound, for example,containing at least 1% by weight anhydride catalyst such as maleicanhydride. Other polymers include protein polymers such as gelatin andfibrin and polysaccharides such as hyaluronic acid. Polylactic acid isnot useful since it takes at least one year to degrade in vivo. Thepolymers should be biocompatible. Biocompatibility is enhanced byrecrystallization of either the monomers forming the polymer and/or thepolymer using standard techniques.

Other local carrier or release systems can also be used, for example,the lecithin microdroplets or liposomes of Haynes, et al.,Anesthesiology 63, 490-499 (1985), or the polymer-phospholipidmicroparticles of U.S. Pat. No. 5,188,837 (Domb), the disclosure ofwhich is hereby incorporated by reference.

The delivery systems may be in the form of microparticles (e.g.,microcapsules and microspheres), beads, pellets, and rods. When thedelivery systems contemplate the use of microparticles, themicroparticles may be in a size and distribution range suitable forimplantation, injection or infiltration. The diameter and shape of themicroparticles can be manipulated to modify the release characteristics.For example, larger diameter microparticles will typically provideslower rates of release and reduced tissue penetration and smallerdiameters of microparticles will produce the opposite effects, relativeto microparticles of different mean diameter, but of the samecomposition. In addition, other particle shapes, such as cylindricalshapes, can also modify release rates by virtue of the increased ratioof surface area to mass inherent to such alternative geometrical shapes,relative to a spherical shape. The diameter of microparticles may rangein size from about 5 microns to about 200 microns in diameter.

In another embodiment, the microparticles may range in diameter fromabout 20 to about 120 microns. In another embodiment of the presentinvention, the compounds can be administered in the form of implantablepellets, rods and slabs. Methods for manufacture of microparticles,pellets, rods and slabs are well known in the art and include solventevaporation, phase separation and fluidized bed coating.

Methods of Treatment

The compound of the invention may be used to provide topical anesthesia,dermal anesthesia, ocular anesthesia, intravenous regional anesthesia,infiltration anesthesia, field block anesthesia, spinal anesthesia andnerve block anesthesia.

The compounds may also be used for treating various disease states andconditions. In certain embodiments, the compounds may be useful forproviding anesthesia to a patient in need thereof by administering thecompound to a specific site, e.g., surgical site or open wound. Incertain embodiments, the compound may be used for providing localanesthesia for minor procedures and before, during and after surgery.For example, it is contemplated that the compounds, e.g., S-LAC-34, maybe used for dental procedures, plastic surgery, arthroscopic procedures,laparoscopic procedures and orthopedic procedures to name a few. Incertain embodiments the compounds may be used for laparoscopiccholecystectomy, hernia repair, bunionectomy, knee replacement surgery,median sternotomy, and mastectomy.

The compounds may also express analgesic activities. In certainembodiments, the compounds may be useful for providing analgesia to apatient in need thereof to treat a painful condition. Conditionsassociated with pain include, but are not limited to, nociceptive pain(pain transmitted across intact neuronal pathways), neuropathic pain(pain caused by damage to neural structures), pain from nerve injury(neuromas and neuromas in continuity), pain from neuralgia (painoriginating from disease and/or inflammation of nerves), pain frommyalgias (pain originating from disease and/or inflammation of muscle),pain associated with painful trigger points, pain from tumors in softtissues, pain associated with neurotransmitter-dysregulation syndromes(disruptions in quantity/quality of neurotransmitter moleculesassociated with signal transmission in normal nerves) and painassociated with orthopedic disorders such as conditions of the foot,knee, hip, spine, shoulders, elbow, hand, head and neck.

The receptors involved in pain detection are aptly enough referred to asnociceptor-receptors for noxious stimuli. These nociceptors are freenerve endings that terminate just below the skin as to detect cutaneouspain. Nociceptors are also located in tendons and joints, for detectionof somatic pain and in body organs to detect visceral pain. Painreceptors are very numerous in the skin, hence pain detection here iswell defined and the source of pain can be easily localized. In tendons,joints, and body organs the pain receptors are fewer. The source of paintherefore is not readily localized. Apparently, the number ofnociceptors also influences the duration of the pain felt. Cutaneouspain typically is of short duration, but may be reactivated upon newimpacts, while somatic and visceral pain is of longer duration. It isimportant to note that almost all body tissue is equipped withnociceptors. As explained above, this is an important fact, as pain hasprimary warning functions, for example, impinging on the well-being ofthe patient and thereby causing the patient to seek medical assistance.Nociceptive pain includes, but is not limited to post-operative pain,cluster headaches, dental pain, surgical pain, pain resulting fromsevere burns, post-partum pain, angina, genitor-urinary tract pain, painassociated with sports injuries (tendonitis, bursitis, etc.) and painassociated with joint degeneration and cystitis.

Neuropathic pain generally involves abnormalities in the nerve itself,such as degeneration of the axon or sheath. For example, in certainneuropathies the cells of the myelin sheath and/or Schwann cells may bedysfunctional, degenerative and may die, while the axon remainsunaffected. Alternatively, in certain neuropathies just the axon isdisturbed, and in certain neuropathies the axons and cells of the myelinsheath and/or Schwann cells are involved. Neuropathies may also bedistinguished by the process by which they occur and their location(e.g. arising in the spinal cord and extending outward or vice versa).Direct injury to the nerves as well as many systemic diseases canproduce this condition including AIDS/HIV, Herpes Zoster, syphilis,diabetes, and various autoimmune diseases. Neuropathic pain is oftendescribed as burning, or shooting type of pain, or tingling or itchingpain and may be unrelenting in its intensity and even more debilitatingthan the initial injury or the disease process that induced it.

Neuropathies treatable by the methods of the present invention include:syndromes of acute ascending motor paralysis with variable disturbanceof sensory function; syndromes of subacute sensorimotor paralysis;syndromes of acquired forms of chronic sensorimotor polyneuropathy;syndromes of determined forms of genetic chronic polyneuropathy;syndromes of recurrent or relapsing polyneuropathy; and syndromes ofmononeuropathy or multiple neuropathies (Adams and Victor, Principles ofNeurology, 4th ed., McGraw-Hill Information Services Company, p. 1036,1989). Syndromes of acute ascending motor paralysis are selected fromthe group-consisting of acute idiopathic polyneuritis,Landry-Guillain-Barre Syndrome, acute immune-mediated polyneuritis,infectious mononucleosis polyneuritis, hepatitis polyneuritis; dipthericpolyneuropathy; porphyric polyneuropathy; toxic polyneuropathy (e.g.,thallium); acute axonal polyneuropathy; acute panautonomic neuropathy;vaccinogenic, serogenic, paraneoplastic, polyarteretic and lupuspolyneuropathy.

Syndromes of subacute sensorimotor paralysis are selected from the groupconsisting of deficiency states (e.g., beriberi, pellagra, vitamin B12);heavy metal/industrial solvent poisonings (e.g., arsenic, lead); drugoverdose (e.g., isoniazid, disulfuram, vincristine, taxol,chloramphenicol); uremic polyneuropathy; diabetes; sarcoidosis; ischemicneuropathy and peripheral vascular disease; AIDS; and radiation(radiotherapy). Syndromes of chronic sensorimotor are selected from thegroup consisting of carcinoma, myeloma and other malignancies;paraproteinemias; uremia; beriberi (usually subacute), diabetes,hypo/hyperthyroidism; connective tissue disease; amyloidosis; leprosyand sepsis. Genetic chronic polyneuropathies are selected from the groupconsisting of dominant mutilating sensory neuropathy (adult); recessivemutilating sensory neuropathy (childhood); congenital insensitivity topain; spinocerebellar degenerations, Riley Day Syndrome; UniversalAnesthesia Syndrome; polyneuropathies w/metabolic disorder; and mixedsensorimotor-autonomic type polyneuropathies. Recurrent/relapsingpolyneuropathy are selected from the group consisting of idiopathicpolyneuritis; porphyria; chronic inflammatory polyradiculoneuropathy;mononeuritis multiplex; beriberi/drug overdose; refsum disease andtangier disease. Mono/multiple neuropathies are selected from the groupconsisting of pressure palsies; traumatic neuropathies (e.g.,irradiationor electrical injury); serum, vaccinogenic (e.g., rabies,smallpox); herpes zoster; neoplastic infiltration; leprosy; dipthereticwound infections; migrant sensory neuropathy; shingles and post herpeticneuralgia.

Neurotransmitter-dysregulation pain syndromes, rather than involvingabnormal or damaged nerves, result from normal nerves having disruptionsin the quantity and/or quality of the various neurotransmitter moleculesassociated with signal transmission from one neuron to another. Morespecifically, sensory transmitters are released from the afferent nerveending of one nerve cell and received by receptors at the afferent endof another nerve cell. They are chemical messengers which transmit thesignal. There are numerous transmitters, including glutamate, serotonin,dopamine, norepinephrine, somatostatin, substance P, calcitoningene-related peptide, cholecystokinin, opiates and saponins. Alterationsin the quantity of transmitters and neuropeptide release, changes in theafferent receptor, changes of re-uptake of the transmitter and/orneuropeptides can all yield qualitative change of the neural signalingprocess. As a result, the aberrant signal transmission is interpreted bythe body as pain. A representative neurotransmitter dysregulationsyndrome that may be treated by the present invention includesfibromyalgia, which is a common condition characterized by a history ofchronic generalized pain and physical exam evidence of at least 11 of 18defined “tender point” sites in muscles and connective tissue (Wolfe etal., Arthritis Rheum 33:160-72, 1990). Commonly associated conditionsinclude irritable bowel syndrome, headache, irritable bladder syndrome(interstitial cystitis), sleep disturbance, and fatigue (Goldenberg,Current Opinion in Rheumatology 8:113-123, 1996; Moldofsky et al.,Psychosom Med 37:341-51, 1975; Wolfe et al., 1990; Wolfe et al., J Rheum23:3, 1996; Yunus et al., Semin Arthritis Rheum 11:151-71, 1981).

A predominant theory regarding the etiology of fibromyalgia holds thatan imbalance and/or dysregulation of neurotransmitter function may occurwithin the central nervous system (CNS), either in the brain or spinalcord and in the relation of the CNS to muscle and connective tissue viaregulatory nerve pathways (Goldenberg, 1996; Russell, Rheum Dis Clin NA15:149-167, 1989; Russell et al., J Rheumatol 19:104-9, 1992; Vaeroy etal., Pain 32:21-6, 1988; Wolfe et al., 1996). Neurotransmitters arechemical messengers, amino acids, biogenic amines and neuropeptides,emitted from nerve cells that interact with receptors on other nervecells, as well as other cell types, including muscle and immune cells.Neurotransmitter imbalance, which leads to increased pain experience,may include a qualitative and/or quantitative decrease in the functionof such neurotransmitters as glutamate, serotonin, dopamine,norepinephrine, somatostatin, substance P, calcitonin gene-relatedpeptide, cholecystokinin, opiates and saponins. Fibromyalgia ischaracterized by a relative deficit of serotonin effect and relativeexcess of substance P effect. This imbalance results in amplifiedmodulation of pain-signaling in the central nervous system, resulting inneurogenic pain (Matucci-Cerinic, Rheumatic Disease Clinics of NorthAmerica 19:975-991, 1993; Bonica, The Management of pain, Lea andFebiger, 2d ed., Philadelphia, pp. 95-121, 1990). Similar mechanisms maybe at work to cause associated conditions; for example, dysregulation ofneurotransmitter signaling in the bowel musculature, leading toirritable bowel syndrome symptoms such as cramping, diarrhea, and/orconstipation.

Neurotransmitter-dysregulation pain syndromes include, but are riotlimited to the following: generalized syndromes, localized syndromes;craniofascial pain; vascular disease; rectal, perineum and externalgenitalia pain; and local syndromes of the leg/foot.

Generalized syndromes are selected from the group consisting of stumppain, causalgia, reflex sympathetic dystrophy, fibromyalgia or diffusemyofascial pain and burns. Localized syndromes are selected from thegroup consisting of trigeminal neuralgia; acute herpes zoster;panautonomic neuralgia; geniculate neuralgia (Romsay Hunt Syndrome);glossopharyngeal neuralgia; vagus nerve neuralgia and occipitalneuralgia. Craniofacial pain includes temporomandibular pain.Suboccipital and cervical musculoskeletal disorders are selected fromthe group consisting of myofascial syndrome, which includes cervicalsprain cervical hyperextension (whiplash); stemocleidomastoid muscle;trapezius muscle; and stylohyoid process syndrome (Eagle's syndrome).Vascular disease is selected from the group consisting of Raynaud'sdisease; Raynaud's phenomenon; frosbite; erythema pernio (chilblains);acrocyanosis and livedo reticularis. Rectal, perineum and externalgenitalia pain are selected from the group consisting of iliohypogastricneuralgia; iliolinguinal nerve; genotifemoral nerve and testicular pain.Local syndromes of the leg/foot are selected from the group consistingof lateral cutaneous neuropathy (neuralgia paresthetica); obturatorneuralgia; femoral neuralgia; sciatica neuralgia; interdigital neuralgiaof the foot (Morton's metatarsalgia or neurma); injection neuropathy andpainful legs and moving toes.

Pain Intensity assessment scales are typically used by those of ordinaryskill in the art to evaluate analgesic choices and therapeutic effects.

A Visual Analogue Scale (VAS) is a measurement instrument that measuresa characteristic that is believed to range across a continuum of valuesand cannot easily be directly measured. For example, the amount of painthat a patient feels ranges across a continuum from none to an extremeamount of pain may be indirectly measured via the use of a VAS.Operationally a VAS is usually a horizontal line, 100 mm in length,anchored by word descriptors at each end, for example “no pain” at oneend and “very severe pain” at the other end. The patient, marks on theline the point that they feel represents their perception of theircurrent state. The VAS score is determined by measuring in millimetersfrom the left hand end of the line to the point that the patient marks.The 100-mm visual analog scale (VAS), a unidimensional scale that isversatile and easy to use, has been adopted in many settings.

Treatment of Chronic Post-Herniorrhaphy Pain

In a preferred embodiment, the compounds may be used for thetreatment/attenuation of chronic post-herniorrhaphy pain. Chronicpost-herniorrhaphy pain occurs in between 5-30% of patients, with socialconsequences limiting some type of activity in about 10% of patients and1-4% of patients are referred to chronic pain clinics. Nerve damage isprobably the most plausible pathogenic factor, but specific principlesfor therapy have not been evidence-based and range from usual analgesicsto re-operation with mesh removal and various types of nerve sectionswithout any demonstrated efficacy in sufficient follow-up studies withor without randomized data. In patients suffering from pain associatedwith chronic post-herniorrhaphy, a dose the compound may be administeredto the site where the surgery was performed or to the immediate areasurrounding the incision.

Treatment of Pain Associated with Morton's Neuroma

In another preferred embodiment, the compounds may be used for thetreatment/attenuation of pain associated with Morton's Neuroma. Morton'sNeuroma is considered to be most likely a mechanically induceddegenerative neuropathy which has a strong predilection for the thirdcommon digital nerve in middle-aged women. It is considered awell-defined model of neuropathic pain. The usual medical treatment ofMorton's neuroma includes local injection of steroids, often withlidocaine. When nonsurgical means fail to relieve patient's symptoms,surgical removal of this offending neuroma through a dorsal approach canproduce dramatic relief of symptoms in approximately 80% of patients.However, 20% of patients experience neuroma recurrence (referred to asstump or amputation neuroma) that often causes more severe pain that theoriginal neuroma and is generally treatment resistant. Administration ofthe compounds in accordance with the invention is useful for thetreatment of the neuropathic pain associated with Morton's Neuroma andmay reduce the re-occurrence of pain associated with stump or amputationneuroma.

Orthopedic Disorders

The compounds of the invention may be utilized to treat/attenuate painassociated with orthopedic disorders. Orthopedic disorders treatable viathe use of the formulations and methods of the invention include but arenot limited to disorders of the knee, shoulders, back, hip, spine,elbows, foot, hand and other disorders, which involve pain at a specificsite or body space. Orthopedic disorders affecting these locationsinclude, but are not limited to bursitis, tendonitis, osteoarthritis,and rheumatoid arthritis. Bursitis is the inflammation of a bursa.Bursae are saclike cavities or potential cavities that contain synovialfluid located at tissue sites where friction occurs (e.g., where tendonsor muscles pass over bony prominences). Bursae facilitate normalmovement, minimize friction between moving parts, and may communicatewith joints. In the normal state, the bursa provides a slippery surfacethat has almost no friction. A problem arises when a bursa becomesinflamed. The bursa loses its gliding capabilities, and becomes more andmore irritated when it is moved. When the condition called bursitisoccurs, the slippery bursa sac becomes swollen and inflamed. The addedbulk of the swollen bursa causes more friction within already confinedspaces. Also, the smooth gliding bursa becomes gritty and rough.Movement of an inflamed bursa are painful and irritating. Bursitisusually occurs in the shoulder (subacromial or subdeltoid bursitis).Other sites include the olecranon (miners' elbow), prepatellar(housemaid's knee) or suprapatellar, retrocalcaneal (Achilles),iliopectineal (iliopsoas) of the hip, ischial (tailor's or weaver'sbottom) of the pelvis, greater trochanteric of the femur, and firstmetatarsal head (bunion). Bursitis may be caused by trauma, chronicoveruse, inflammatory arthritis (eg, gout, rheumatoid arthritis), oracute or chronic infection (eg, pyogenic organisms, particularlyStaphylococcus aureus; tuberculous organisms; which now rarely causebursitis). Orthopedic disorders of the foot include, but are not limitedto, heel spurs, corns, bunions, Morton's neuroma, hammertoes, anklesprain, fractures of the ankle or metatarsals or sesamoid bone or toes,plantar fascitis and injuries to the achilles tendon. Orthopedicdisorders of the hand include, but are not limited to, arthritis, carpaltunnel syndrome, ganglion cysts, tendon problems such as lateralepicondylitis, medial epicondylitis, rotator cuff tendonitis,DeQuervian's tenosynovitis, and trigger finger/trigger thumb. Otherorthopedic disorders include, but are not limited to, Paget's disease,scoliosis, soft-tissue injuries such as contusions, sprains and strains,long bone fractures and various other sports injuries some of whichinclude patellar tendonitis and lumbar strain.

Treatment of non-infected acute bursitis has mainly consisted oftemporary rest or immobilization and high-dose NSAIDs, sometimesnarcotic analgesics, may be helpful. Voluntary movement should beincreased as pain subsides. Pendulum exercises are particularly helpfulfor the shoulder joint. Aspiration and intrabursal injection of depotcorticosteroids 0.5 to 1 ml (triamcinolone diacetate 25 or 40 mg/ml)mixed with at least 3 to 5 ml of local anesthetic after infiltrationwith 1% local anesthetic (e.g., lidocaine) is the treatment of choicewhen rest alone is inadequate. The depot corticosteroid dose and volumeof mixture are gauged to the size of the bursa. Reaspiration andinjection may be required with resistant inflammation. Systemiccorticosteroids (prednisone 15 to 30 mg/day or equivalent for 3 days)are occasionally indicated in resistant acute cases after infection andgout have been excluded. Chronic bursitis is treated as acute bursitis,except that splinting and rest are less likely to be helpful. Surgery israrely needed to treat bursitis and is usually done only in the chroniccases that have not improved with traditional therapy. The most commonsurgical treatment, if needed, is an Incision and Drainage (called an Iand D) and is used only in cases of infected bursa. The surgeon firstnumbs the skin with an anesthetic and then opens the bursa with ascalpel. Finally, the surgeon drains the fluid present in the inflamedbursa. Sometimes it is necessary to excise the entire bursa surgically.This is indicated only if the bursal swelling causes problems.

The compound may be administered via injection in a location and fashionsimilar to that currently utilized with respect to localized injectionsof corticosteroids. For example, in certain embodiments, the dose of thecompound may be administered by intra-articular injection into thebursa.

Tendonitis

The compounds of the invention may be utilized to treat/attenuate painassociated with tendonitis (inflammation of the tendons). When tendonsbecome inflamed, the action of pulling the muscle becomes irritating andpainful. The cause is often unknown. Most instances tendonitis occurs inmiddle-aged or older persons as the vascularity of tendons attenuates;repetitive microtrauma may increase injury. Repeated or extreme trauma(short of rupture), strain, or excessive (unaccustomed) exercise is mostfrequently implicated. The most common cause of tendonitis is overuse.Commonly, individuals begin an exercise program, or increase their levelof exercise, and begin to experience symptoms of tendonitis. The tendonis unaccustomed to the new level of demand, and this overuse will causean inflammation and tendonitis. Tendonitis produces pain, tenderness andstiffness near a joint which is aggravated by movement.

General practitioners commonly use non-steroidal anti-inflammatory drugs(NSAIDs) to treat tennis elbow, but there are no trials to date thathave compared them with other painkillers and one study found noclinically important benefit over placebo. Symptomatic relief isprovided by rest or immobilization (splint or cast) of the tendon,application of heat for chronic inflammation or cold for acuteinflammation (whichever benefits the patient should be used), localanalgesic drugs, and NSAIDs for 7 to 10 days. A critical review of therole of various anti-inflammatory medications in tendon disorders foundlimited evidence of short-term pain relief and no evidence of theireffectiveness in providing even medium term clinical resolution. Use ofcorticosteroid injections provides mixed results in relief of pain andat times insufficient evidence to support their use. Injection of thetendon sheath with a depot corticosteroid (e.g., dexamethasone acetate,methylprednisolone acetate, hydrocortisone acetate) 0.5 to 1 ml mixedwith an equal or double volume of 1% local anesthetic (e.g., lidocaine)has been utilized as a treatment, depending on severity and site. Theinjection is made blindly or proximal to the site of maximum tendernessif the specific inflammation site cannot be identified. Particular careshould be taken not to inject the tendon per se (which offers greaterresistance) because it may be weakened and rupture in active persons.Reexamination of a less inflamed site 3 or 4 days later often disclosesthe specific lesion, and a second injection can be made with greaterprecision. Rest of the injected part is advisable to diminish risk oftendon rupture. Although complications associated with intraarticularand soft tissue steroid injection are relatively uncommon, when acomplication does occur, it can result in severe and disablingconsequences for the subject. A small proportion of subjects fail torespond to only one injection of corticosteroid and some subjects whoinitially improve at four weeks had worst symptoms by six months.Therefore with this lack of consensus, no good evidence to support theuse of local corticosteroid injections and the unknown long-termside-effects of using steroids, an alternative treatment must be sought.

In one embodiment of the present invention, pain associated withtendonitis of the knee, shoulders, hip, pelvis, spine, elbows, leg andfoot may be treated with the compounds by injecting the compound insimilar fashion as a localized corticosteroid injection. For example, inembodiments where the compound is used for the treatment/attenuation ofpain associated with tendonitis or bursitis of the shoulder, a dose ofthe compound can be administered by injection into the subacromial bursawith the needle inserted into the space between the acromium and thehumerus on the lateral aspect of the shoulder.

Osteoarthritis

The compounds of the present invention may be used to treat/attenuatepain associated with osteoarthritis (degenerative joint disease).Osteoarthritis is characterized by the breakdown of the joint'scartilage. Cartilage is the part of the joint that cushions the ends ofbones. Cartilage breakdown causes bones to rub against each other,causing pain and loss of movement. Most commonly affecting middle-agedand older people, osteoarthritis can range from very mild to verysevere. It affects hands and weight-bearing joints such as knees, hips,feet and the back. There are many factors that can cause osteoarthritis,including but not limited to age, genetics, obesity, sports-relatedactivities, work-related activities, or accidents. Treatment ofosteoarthritis focuses on decreasing pain and improving joint movement,and may include: Exercises to keep joints flexible and improve musclestrength; many different medications are used to control pain, includingcorticosteroids and NSAIDs, glucocorticoids injected into joints thatare inflamed and not responsive to NSAIDS. For mild pain withoutinflammation, acetaminophen may be used; heat/cold therapy for temporarypain relief, joint protection to prevent strain or stress on painfuljoints; surgery (sometimes) to relieve chronic pain in damaged joints;and weight control to prevent extra stress on weight-bearing joints.

Pain associated with osteoarthritis may be treated/attenuated with thecompounds administered, e.g., by intra-articular injection at theaffected site, including but not limited to orthopedic disorders of theknee such as osteoarthritis, shin splints, medial tibial stresssyndrome, bursitis, tendonitis (patellar tendonitis); tears of theanterior cruciate ligament (blown out knee), posterior cruciateligament, medial collateral ligament and lateral collateral ligament;arthritis of the knee; meniscal cartilage tear; Runner's conditions suchas iliotibial band syndrome and Pes Anserine bursitis; torn meniscus andlimited cartilage defects of the knee; orthopedic disorders of theshoulders including, but not limited to, bursitis, dislocation,separation, impingement and tear of the rotator cuff, tendonitis,adhesive capsulitis (frozen shoulder) and fractures.

Rheumatoid Arthritis

The compounds may be used to treat/attenuate pain associated withrheumatoid arthritis. Rheumatoid arthritis is a chronic, systemic,inflammatory disease that chiefly affects the synovial membranes ofmultiple joints in the body. Because the disease is systemic, there aremany extra-articular features of the disease as well. RheumatoidArthritis can affect many joints in the body, including the knee, ankle,elbow, and wrist. Joints that are actively involved with the disease areusually tender, swollen, and likely demonstrate reduced motion. Thedisease is considered an autoimmune disease that is acquired and inwhich genetic factors appear to play a role. The compounds may beadministered via intra-articular injection in a location and fashionsimilar to that currently utilized with respect to localized injectionsof corticosteroids.

There are several different classes of drugs utilized to treat patientswith the various types of rheumatic disease which maybe used in additionto treatment with the compounds of the present invention, includinganalgesics to control pain, corticosteroids, uric acid-lowering drugs,immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, anddisease-modifying antirheumatic drugs.

Back Pain

The compounds may be used to treat/attenuate pain associated with backpain. Back pain is the second most common reason for doctor visits inthe U.S. The causes of lower back pain are numerous. Some of the morecommon causes of lower back pain are: sudden injury to the back such asmay occur in an auto accident, fall, sports, or other manner;gynecological conditions such as endometriosis, menstrual cramps,fibroid tumors, and pregnancy are sometimes the cause of lower back painin women; and stress to the muscles, nerves, or ligaments in the lowerback. Slipped discs, pinched nerves, sciatica, aging, and infections areother common causes of lower back pain. The treatment of lumbar strainconsists of resting the back (to avoid re-injury), medications torelieve pain and muscle spasm, local heat applications, massage, andeventual (after the acute episode resolves) reconditioning exercises tostrengthen the low back and abdominal muscles Zygapophysial joints,better known as facet or “Z” joints, are located on the back (posterior)of the spine on each side of the vertebrae where it overlaps theneighboring vertebrae. The facet joints provide stability and give thespine the ability to bend and twist. They are made up of the twosurfaces of the adjacent vertebrae, which are separated by a thin layerof cartilage. The joint is surrounded by a sac-like capsule and isfilled with synovial fluid (a lubricating liquid that reduces thefriction between the two bone surfaces when the spine moves and alsonourishes the cartilage). A problem (such as inflammation, irritation,swelling or arthritis) in the facet joint may cause low back pain.Diagnostic tests can show an abnormality in a facet joint, which maysuggest that the facet joint is the source of the pain. However,sometimes normal study results can be present while the facet joint isstill the source of pain, and abnormal results do not always implicatethe facet joint.

To determine if a facet joint is truly the source of back pain, aninjection of local anesthetic (e.g., as a block) may be utilized. If aninjection of a small amount of anesthetic or numbing medication into thefacet joint reduces or removes the pain, it indicates that the facetjoint may be the source of the pain. This is diagnostic use of the facetjoint injection. Once a facet joint is pinpointed as a source of pain,therapeutic injections of anesthetic agents and anti-inflammatorymedications may give pain relief for longer periods of time. Thecompounds may be administered in such situations to attenuate such pain.

Facet joint injections are performed while the patient is awake, under alocal anesthetic, and able to communicate. Sometimes, the health careprovider may also administer drugs to make the patient more comfortableduring the procedure. The injection is usually performed while thepatient is lying on his or her stomach on an X-ray table. EKG, bloodpressure cuffs and blood-oxygen monitoring devices may be hooked upprior to the injection process. Once the proper site has beendetermined, the physician will inject the anesthetic (often lidocaine orbupivicaine) and the anti-inflammatory (usually a corticosteroid.). Thisprocess may then be repeated depending on the number of affected facetjoints.

The compounds may be administered via injection to treat back pain,e.g., in a location and fashion similar to that currently utilized withrespect to localized injections of corticosteroids.

Heel Spur

The compounds of the present invention may be used to treat/attenuatepain associated with a heel spur, which is a projection or growth ofbone where certain muscles and soft tissue structures of the foot attachto the bottom of the heel. Most commonly, the plantar fascia, a broad,ligament-like structure extending from the heel bone to the base of thetoes becomes inflamed, and symptoms of heel pain begin. As thisinflammation continues over a period of time, with or without treatment,a heel spur is likely to form. If heel pain is treated early,conservative therapy is often successful arid surgery is usuallyavoided. Early signs of heel pain are usually due to plantar fasciitis,the inflammation of the plantar fascia. It is probably the most commoncause of heel pain seen by the podiatrist. It is seen in all groups ofpeople; runners, athletes, week-end warriors, people who have jobsrequiring a fair amount of standing, walking, or lifting, and those whohave recently gained weight. Initially, patients receive taping of thefoot and when indicated, cortisone injections or a short course ananti-inflammatory medication, taken orally. Exercises, night splints,and physical therapy are used as adjunct methods to try to reduce theinflammation. If successful, a custom made in shoe orthotic is made tocontrol the abnormal stress and strain on the plantar fascia resultingin remission of the majority of the symptoms.

When the compound is used for the treatment of plantar fascia, the doseof the compound is preferably administered by injection into theaffected area. When surgery is required, the compound is preferablyadministered by infiltration into the heel bone.

Laparoscopic Cholecystectomy

The compounds may be used to treat/attenuate pain associated withlaparoscopic cholecystectomy. Laparoscopic cholecystectomies havevirtually replaced open surgical cholecystectomy. However, patientsundergoing laparoscopic cholecystectomies still have pain. Pain controlfollowing surgery typically includes use of opioids, especially withinthe first several days after surgery. The administration of thecompounds in a patient who has undergone a laparoscopic cholecystectomymay reduce the amount of opioid consumption and postoperative painscores associated with the procedure. In patients suffering from painassociated with a laparoscopic cholecystectomy, the dose of the compoundmay be administered either by injection, infiltration or both injectionand infiltration. When the dose of compound is administered byinjection, the compound may be injected directly the site of incision orto the immediate area surrounding the surgical site.

The compounds may be used to treat/attenuate pain associated with otherlaparoscopic surgical procedures, as well.

In further embodiments, the compounds of the present invention may beuseful for improving sleep. The improved sleep may be a direct result ofthe effectiveness of the compounds to reduce and/or alleviate pain,e.g., neuropathic pain thus allowing a patient to experienced improvedsleep.

The compounds may be administered as a single dose in a therapeuticallyeffective amount to a discrete site in a patient in need thereof Inother embodiments, the compounds may be administered in multiple dosesto obtain the desired pharmacological effect. The quantity of compoundto be administered will be determined on an individual basis, and willbe based on the pharmacological potency of the drug, the route ofadministration and at least in part on consideration of the individual'ssize, the severity of the symptoms to be treated and the results sought.In general, quantities of the compound sufficient to eliminate theunwanted condition will be administered. The actual dosage(concentration and volume) and the number of administrations per daywill depend on the pharmacokinetic properties to be achieved (anesthesiaor analgesia) and the mode of drug administrations, for example, bytopical doses to the eye or the mucous membranes of the mouth, or bydermal application to the skin or by injections to achieve infiltrationanesthesia or nerve blocks.

Administration of the compounds according to the methods of the presentinvention provides for a long duration of anesthesia/analgesia. Incomparison, the duration of action of these compounds is longer whencompared to lidocaine, the R-isomer and the racemic mixture whenadministered at the same concentration. In certain embodiments,administration of the compounds according to the methods of the presentinvention provides anesthesia/analgesia for at least about 5 minutes toabout 48 hours. In other embodiments, administration of the compoundsmay provide anesthesia and/or analgesia for about 15 minutes to about 24hours. In certain embodiments a depot formulation may provide anesthesiaand/or analgesia for about 24 hours to about 26 weeks, e.g., parenteraladministration.

Since the S-isomer offers a long duration of local anesthesia/analgesia,even without the use of vasoconstrictors, and since the compounds haveinherent analgesic activity, these compounds may be suited forcombination with other active agents. For example, injectable solutionsmay contain a vasoconstrictor (e.g. epinephrine or vasopressin); asolution for infusion or regional anesthesia may contain glucose ordextrose, a jelly for urogenital topical procedures may containthickening agents (e.g. hydroxypropylmethylcellulose); a preparation fortopical or dermal application may contain penetration promoting agents(e.g. hydroxypolyethoxydodecane, DMSO, DMAC); sprays for topicalanesthesia of the mouth and oropharynx may contain saccharin andalcohol, ointments for accessible mucous membranes may contain alubricant. The compound of the invention can also be administeredtogether with other membrane stabilizers (local anesthetics), forexample to form eutectic mixtures.

In certain embodiments, the compounds may be suitable forco-administration with other analgesic drugs such as, but not limitedto, opioid analgesics, steroidal or non-steroidal anti-inflammatoryagents and salicylates. In other embodiments, the compounds may beco-administered with capsaicinoids such as capsaicin. In combinationwith capsaicin, the compounds may offer improved analgesic activitywithout the initial pain associated with capsaicinoid administration.

In certain embodiments, co-administration of capsaicin with a compoundof the present invention, e.g., S-LAC-34, may a provide for apotentiation of the local anesthetic activity of the compound. In otherembodiments, co-administration of these two agents may provide animprovement of the therapeutic response in a patient suffering fromneuropathic pain.

In certain embodiments, the concentration of capsaicinoid may range fromabout 0.0001% to about 10% percent. In other embodiments, theconcentration of capsaicinoid may range from about 0.01% to 1%. In otherembodiments, the capsaicinoid may range from about 0.1% to 1%.

The co-administration of a compound of the present invention withadditional analgesic agents may be valuable in patients suffering fromchronic pain.

In other embodiments of the present invention, the compounds may beco-administered with vasoconstrictor agents, the spreading agenthyaluronidase and/or hyaluronic acid.

When a dose of the compound is administered parenterally via injectionor implantation, the injection or implantation volume of will depend onthe localized site of administration. Suitable injection andimplantation volumes to be delivered range from about 0.1 to about 20ml. In certain embodiments, the injection or implantation volume may befrom about 0.5 to about 10 ml and in other embodiments from about 1.0 toabout 5 ml, depending on the site to be treated.

Volumes for administration via infiltration may range from 0.1 to 1000ml. In other embodiments, infiltration volumes range from 1 ml to about100 ml and from about 5 ml to about 30 ml.

Preparation of the S-Isomers

There are several strategies to prepare enantiomers of drugs. Theseinclude: i) resolution of the racemate drug, for example by fractionalcrystallization of diastereomeric derivatives; ii) separation of theracemate by chiral chromatography; iii) synthesis of the desiredenantiomer by using a chiral starting material; and iv) generation ofthe chiral center by synthesis with a chiral auxiliary molecule. Allfour strategies may be used to prepare S-LAC-34. Three of the strategies(i-iii) are further described herein.

Depending on the process conditions and the starting materials, the endproduct may be obtained either as the free base, polymorh(s),metabolite, derivatives or as an acid addition salt thereof. In certainembodiments, the basic, neutral or mixed salts may be obtained, as wellas hemi-, mono-, sesqui-, or polyhydrates. The acid addition salts ofthe compounds described herein may be transformed in a manner known perse into the free base using basic agents such as an alkali or by ionexchange. In certain embodiments, the free bases obtained may form saltswith organic or inorganic acids.

The preparation of acid addition salts may be performed using acidswhich form suitable therapeutically acceptable salts. Such acidsinclude, but are not limited to hydrohalogen acids, sulfuric,phosphoric, nitric, and perchloric acids; aliphatic, alicyclic,aromatic, heterocyclic carboxy or sulfonic acids, such as acetic,formic, propionic, succinic, glycolic, lactic, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic,p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic orp-aminosalicylic acid, embonic, methanesulfonic, ethane sulfonic,hydroxyethanesulphonc, ethylenesulphonic, halogenbenzenesulphonic,toluenesulfonic, naphtylsulfonic, or sulfanilic acids; methionine,tryptophane, lysine or arginine.

In certain embodiments of the present invention, the compounds of thepresent invention may be prepared by reaction between two agents, one ofwhich is an S-enantiomer. For example, the compounds may be preparedaccording to the following methods:

a) by reacting a compound of formula 2

with an S-enantiomer of a compound of formula 3,

wherein R₁ represents a lower alkyl or hydroxyalkyl containing 1 to 4carbon atoms or a substituted or unsubstituted phenyl and X is a halogen(bromo, chloro, fluoro, iodo) or a reactive esterified hydroxyl group,to form a compound of formula 1; and

b) hydrogenating a compound of formula 1, wherein R₁ is a residueremovable by means of hydrogenolysis to give a compound of formula 1,wherein R₁ is hydrogen; and

c) hydrolyzing a compound of formula 1, wherein R₁ is a residueremovable by means of hydrolysis, to form a compound of formula 1,wherein R₁ is hydrogen; and

d) transforming free bases obtained into their salts or transformingsalts into their free bases.

In certain other embodiments of the present invention, S-LAC-34 may beprepared by: (a) sequential conversion of a N-protected L-pipecolicacid, i.e., the S-enantiomer, to a corresponding diazomethyl ketone. Thecorresponding ketone is then converted to a methyl ester and the methylester then converted to a primary alcohol. The primary alcohol is thenconverted to an S-alkyl halide; (b) reacting the resulting S-alkylhalide with 2-(phenylamino)indane; and (c) removing the N-protectinggroup to obtain S-LAC-34.

In certain other embodiments, the S-LAC-34 of the present invention maybe prepared by: (a) sequential conversion of a N-protected L-pipecolicacid to a corresponding diazomethyl ketone. The corresponding ketone isthen converted to a methyl ester and the methyl ester then converted toa primary alcohol. The primary alcohol is then converted to an S-alkylhalide; (b) removing the N-protecting group; (c) introducing a different(second) protecting group; (d) reacting the resulting S-alkyl halidewith 2-(phenylamino)indane, and (e) removing the N-protecting group toobtain S-LAC-34.

In yet another embodiment, the S-LAC-34 of the present invention may beprepared by: (a) sequential conversion of a N-protected L-pipecolic acidto a corresponding diazomethyl ketone. The corresponding ketone is thenconverted to a methyl ester and the methyl ester then converted to aprimary alcohol. The primary alcohol is then converted to an S-alkylhalide; (b) removing the N-protecting group; and reacting the resultingS-alkyl halide, as a salt, with 2-(phenylamino)indane.

The N-protecting group may be benzyl or benzyloxycarbonyl. When theN-protecting group is benzyl, the benzyl may be removed byhydrogenolysis. When the N-protecting group is benzylkoxycarbonyl, thebenzyloxycarbonyl may be removed by acid hydrolysis.

In certain embodiments, S-2-(2-haloethyl)piperidine salt isS-2-(chloroethyl)piperidine hydrochloride. TheS-2-(chloroethyl)piperidine hydrochloride may be combined with2-(phenylamino)indane in the presence or absence of, independently, asolvent and a catalyst.

The mixture may be heated to a temperature of from about 120° C. toabout 160° C. for a time period of from about 24 hours to about 72hours. The 2-(phenylamino)indane and S-2-(2-chloroethyl)piperidinehydrochloride may be combined with 1,3-dimethylimidazolidinone in thepresence of 2,6-lutidine. The resulting mixture may then be heated to atemperature of from about 120° C. to about 160° C. under an atmosphereof nitrogen for a period of from about 24 hours to about 72 hours withconstant stirring. Solvent may then be added and the mixture heated.Once heated the hydrochloride salt of the mixture may be cooled andfiltered to obtain the S-LAC-34.

In certain other embodiments, S-LAC-34 may be prepared by resolution ofracemic LAC-34 by fractional crystallization of a diastereomeric saltswith chiral acids. In certain embodiments, the chiral acid may beselected from the group consisting of tartaric acid,di-(p-toluyl)-tartaric acid, dibenzoyl-tartaric acid or mandelic acid.

In certain embodiments, S-LAC-34 may be prepared by separation of theenantiomers from racemic LAC-34 using chromatography on a chiralsupport. The chiral support may be HPLC or column chromatography.

The invention is more fully understood by the following examples.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34) has nowbeen synthesized according to the following methodology.(Boc=benzyloxycarbonyl).

EXAMPLE I The Synthesis of (S)-LAC-34 Hydrochloride from Chiral StartingMaterial

Isobutyl chloroformate (5.65 ml) was added dropwise to a solution of 9 gof Boc-L-pipecolic acid [1] and 4.97 ml of N-methylmorpholine in 150 mlof anhydrous tetrahydrofuran (THF) at −30° C., and the reaction mixturewas kept at −30° C. for 1 hour. Then 250 ml of a solution ofdiazomethane (prepared from 43 g of diazogen) in diethyl ether wasadded, and the mixture was stirred at room temperature overnight. Aceticacid (5 ml) was added dropwise to destroy excess diazomethane, and thereaction mixture was evaporated to dryness. The residue was dissolved indiethyl ether, washed with water, brine, and dried over Na₂SO₄. Afterevaporation, 8.9 g of crude diazomethyl ketone [2] was obtained, andused directly in the next step.

Compound [2] (8.9 g) was dissolved in 100 ml anhydrous methanol, and 1.0g of silver benzoate was added with stirring at room temperature. After3 hours, 50 ml of brine was added, and the mixture was filtered throughCelite. The filtrate was evaporated to remove methanol, and theresulting aqueous solution was extracted with ethyl acetate three times,the combined organic extract washed with brine, and dried over Na₂SO₄.The dried organic layer was evaporated, and the residue was purified bycolumn chromatography (silica gel) to give 7.64 g of N-Boc β-amino acidester [3].

Lithium aluminum hydride (0.453 g) was added to a solution of 4.0 g ofcompound [3] in 100 ml of anhydrous diethyl ether at 0° C. Thesuspension was stirred at 0° C. for 1 hour, and then poured ontoice-water. The mixture was filtered, and the filtrate was extracted withdiethyl ether three times. The combined organic extract was washed withbrine and dried over Na₂SO₄. After evaporation, 3.48 g of crude alcohol[4] was obtained and used in the next step without purification.

Compound [4] (3.48 g) was dissolved in 15 ml of dichloromethane, and 30ml of 40% trifluoroacetic acid in dichloromethane was added at 0° C.After 2 hours, excess trifluoroacetic acid and solvent were removed invacuo, and the residual salt [5] was dried under high vacuum overnight.

A mixture of compound [5], 2.3 ml of benzyl bromide, 5 g of potassiumcarbonate in 00 ml of acetonitrile was refluxed overnight. The solventwas removed in vacuo, and 2N hydrochloric acid was added until the pHwas ˜4. The mixture was extracted with diethyl ether to remove neutralimpurities. The aqueous layer was neutralized with 2N sodium hydroxideto pH-8, extracted with ethyl acetate three times, the combined organicextract washed with water, brine, and dried over Na₂SO₄. The organiclayer was evaporated to dryness to give 2.5 g of N-benzyl protectedalcohol [6].

A solution of compound [6] (2.5 g), 3 ml of thionyl chloride, two dropsof concentrated hydrochloric acid in 50 ml of chloroform was heated atreflux overnight. The mixture was evaporated to dryness, and 50 ml ofsaturated aqueous sodium bicarbonate was added. The aqueous layer wasextracted with ethyl acetate three times, and the combined organicextract was washed with water, brine, and dried over Na₂SO₄. Afterevaporation, the residue was purified by column chromatography (silicagel) to give 1.7 g of the corresponding alkyl chloride [7].

A suspension of 2-aminophenylindane (1.7 g) and 0.4 g of sodium amide in40 ml of anhydrous toluene was stirred at room temperature for 3 hours.A solution of 1.7 g of compound [7] in 5 ml of anhydrous toluene wasadded. The reaction mixture was refluxed overnight and poured ontoice-water after cooling. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was washed and dried overNa₂SO₄. After evaporation, 1.1 g of pure N-benzyl (S)-LAC-34 [8] wasobtained by column chromatography (silica gel).

A mixture of 1.1 g of compound [8] and 200 mg of 10% Pd—C in 50 ml ofethyl acetate was stirred under 30 psi of hydrogen gas at roomtemperature for 5 hours. The reaction mixture was filtered throughCelite, and the filtrate was evaporated to dryness. The residue wasdissolved in 10 ml of anhydrous diethyl ether, and 10 ml of 2N hydrogenchloride in diethyl ether was added. The 650 mg of desired (S)-LAC-34hydrochloride [9] was obtained by filtration.

¹H NMR (CDCl₃) δ: 7.15˜7.27 (m, 6H, H-Ph), 6.74˜6.86 (m, 3H, H-Ph),4.51˜4.68 (m, 1H, PhNCH), 2.4˜3.40 (m, 10H, C₆H₄(CH₂ )₂—, PhNCH₂ —,—CHNCH₂ —), 1.25˜1.77 (m, 8H, —NCH₂ CH₂CH₂CH₂ —, —NCH₂ CH₂ —).

Biological Testing EXAMPLE II Topical Anesthetic Activity

Aliquots (0.25 ml) of test solutions are applied into the conjunctivalsac of conscious rabbits (either sex; 2-4 kg) and the eye-lids are keptclosed for approximately 20 sec. The corneal reflex is checked beforeapplication of the test solution and every 5 min thereafter. To test thecorneal reflex, the cornea is touched six times with a stalked elasticbristle. The duration of anesthesia is calculated as the period from thetime-point when the animal does not feel any of the six touches by thebristle to the time point when the animal again reacts to three of thesix touches. To verify the reversibility of the topical anestheticeffect, the testing is continued until the animal reacts to all sixtouches of the bristle.

EXAMPLE III Dermal Anesthetic Activity

Approximately 18-24 hours before each experiment, the skin on the backof male or female guinea pigs was shaved and depilated with acommercially available hair remover. The anesthetic action of each agentfollowing dermal application was determined using a “pin-prick” methodas described by Aberg (Acta Pharmacol Toxicol, 1972, 31: 273-286).Before and at various intervals after treatment, the area of the skinwas tested for the presence or absence of a skin twitch in response tosix standardized dermal probings with a pointed metal “algesimeter” at apredetermined maximum load of 10 grams. The average number of probingsnot producing a skin twitch response was designated as the “anestheticscore”. In this test system no response to six stimuli represents a“maximal anesthetic activity”. In the present calculations, the dermalanesthetic activity was calculated from the time of removal of the testarticle formulation from the skin until skin twitch responses to all butone pinprick were identified. In experiments on the dermal anestheticactivity, a single area of skin 1 inch square was marked off on themiddle of the back of each animal. This area was covered by a 1 inchsquare, 16 layer thick gauze pad onto which was deposited 0.45 ml of a10% solution of the test agent dissolved in a mixture of water and DMSO.The gauze pad was covered with a 1.5 inch square sheet of Saran Wrap™which was attached to the surrounding skin with tape. The entire areawas then covered by wrapping an elastic bandage around the trunk of theanimal. After a predetermined duration of treatment, the coverings wereremoved and the skin assessed for the presence of anesthesia asdescribed above. Dermal anesthesia tests were performed at ten-minuteintervals to measure onset time and duration of dermal anestheticactivity; comparisons were made with reference compounds and vehicle.All test compounds were in the base form and dissolved in DMSO/waterwhen tested for dermal anesthesia.

EXAMPLE IV Local (Infiltration) Anesthetic Activity

Approximately 18-24 hours before each experiment, the skin on the backof male guinea pigs is shaved and depilated with a commerciallyavailable hair remover. The anesthetic action of each agent followingintradermal injection is determined using a “pin-prick” method asdescribed by Aberg (Acta Pharmacol Toxicol, 1972, 31: 273-286). Beforeand at various intervals after treatment, the area of the skin is testedfor the presence or absence of skin twitch in responses to sixstandardized cutaneous probings with a pointed metal “algesimeter” at apredetermined maximum force of 20 grams. The average number of probingsnot producing a skin twitch response is designated as the “anestheticscore”. In this test system six responses to six stimuli represents “noanesthetic activity” and no response to six stimuli represents a“maximal anesthetic activity”. In experiments with intradermalinjections, the backs of the guinea pigs are divided into four sectionsusing a marking pen, and injections of 0.1 ml of 0.25%, 0.5% and 1.0%solutions of the test compounds as salts in physiological saline,vehicle (physiological saline) and at least one reference compound aremade, one injection into each of the four defined areas.

EXAMPLE V Analgesic Activity: Effects on Mononeuropathic Pain Thresholds

Peripheral mononeuropathy is induced in rats by loose ligation of thesciatic nerve in anesthetized rats. Fourteen days later, the nociceptivethreshold is evaluated after animal dosing with drug or vehicle, usinggraded paw pressure testing to assess hyperalgesia.

EXAMPLE VI Analgesic Activity: Effects on Diabetic Neuropathic PainThresholds

Diabetes is induced in rats by intraperitoneal injection ofstreptozotocin. Three weeks later, the nociceptive threshold is measuredafter animal dosing using the paw pressure to assess hyperalgesia.

EXAMPLE VII Acute Intravenous Toxicity in Mice

Mice (males) of the NMRI strain, weighing 20 grams to 22 grams are usedafter a stabilization period of at least ten days at the testingfacility and at least one hour in the laboratory. Food but not water iswithheld from all animals for 16 hours before the test. The animals areagain given free access to food starting two hours after the drugadministration that usually takes place around 9.00 AM. All animals areobserved daily for 7 days post dosing.

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. The compound of thepresent invention may be used also for other indications, such as forexample to prevent or treat smooth muscle spasms, cardiac arrhythmias,convulsions and hiccup. Formulations of the compound of the inventionmay also include liposomal formulation, particularly in formulationsused for dermal anesthesia and dermal analgesia. Eutectic formulationscan be obtained by mixing the compound of the formulation with othertherapeutic or chemical entities. All equivalents are intended to beencompassed in the scope of the present invention.

1. A substantially pure S-isomer of a compound having the formula:

or a pharmaceutically acceptable salt, base, or mixture thereof, whereinn is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or anoxygen atom, the (CH₂)_(n) group having a straight or branched chain, Brepresents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms ora group of the formula

in which R₃ and R₄ may independently be selected from the groupconsisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radicalcontaining 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen,A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenylradical substituted by at least one substituent in the ortho, metaand/or para position, and R₁ represents a hydrogen, or a lower alkyl orhydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleusis attached at the 2-, 3-, or 4-position, wherein the compound is usefulfor inducing anesthesia and analgesia in a patient in need thereof. 2.The compound of claim 1, wherein the compound comprises more than 95% ormore S-isomer.
 3. The compound of claim 1, wherein the compoundcomprises more than 97% or more S-isomer.
 4. The compound of claim 1,wherein the compound comprises more than 99% or more S-isomer.
 5. Thecompound of claim 1, wherein the compound isS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34).
 6. Thecompound of claim 1, wherein the pharmaceutically acceptable salt isselected from the group consisting of the monohydrochloride,dihydrochloride, mesylate, lactate, acetate, and sulfamate.
 7. Apharmaceutical formulation for providing anesthesia and analgesia in apatient in need thereof, comprising: a therapeutically effective amountof substantially pure S-isomer of a compound of formula

or pharmaceutically acceptable salt, base, or mixture thereof, wherein nis equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygenatom, the (CH₂)_(n) group having a straight or branched chain, Brepresents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms ora group of the formula

in which R₃ and R₄ may independently be selected from the groupconsisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radicalcontaining 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen,A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenylradical substituted by at least one substituent in the ortho, metaand/or para position, and R₁ represents a hydrogen, or a lower alkyl orhydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleusis attached at the 2-, 3-, or 4-position, and a pharmaceuticallyacceptable excipient.
 8. The formulation of claim 7, wherein thecompound is S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine(S-LAC-34).
 9. The formulation of claim 7, wherein the compoundcomprises 95% or more S-isomer.
 10. The formulation of claim 9, whereinthe therapeutically effective amount is an amount effective for inducinganesthesia in a patient in need thereof upon administration.
 11. Theformulation of claim 9, wherein the therapeutically effective amount isan amount effective for providing analgesia or alleviating pain in apatient in need thereof upon administration.
 12. The formulation ofclaim 9, wherein the formulation is suitable for oral, sublingual,parenteral, topical, transdermal, ocular, intranasal, aural,intrarespiratory, rectal, vaginal, and urethral administration.
 13. Theformulation of claim 12, wherein the formulation is suitable forparenteral administration and the parenteral administration is selectedfrom the group consisting of intravenous, intra-arterial, intracardiac,intraspinal, intraosseous, intra-articular, intrasynovial, subcutaneous,intradermal, and intramuscular injection, implantation, infiltration orinfusion. 14-43. (canceled)
 44. A method of relieving neuropathic painin a patient in need thereof, comprising administering to a discretesite in a patient in need thereof a neuropathic pain-relieving effectiveamount of the compoundS-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine:

wherein administration of the compound to the discrete site provides aduration of action that is longer than that of the correspondingracemate and the corresponding R-isomer, and said compound isco-administered with at least one additional active agent.
 45. Themethod of claim 44, wherein the additional active agent is selected fromthe group consisting of vasoconstrictor, a n analgesic, aglucocorticosteroid, an antihistamine, a local anesthetic, phenol, acapsaicinoid, a spreading or diffusing agent and a viscoelastic agent.46-68. (canceled)
 69. A method of improving sleep in a patient in needthereof, comprising: administering to a discrete site in a patient inneed thereof an anesthetic inducing amount of a substantially pureS-isomer of a compound of formula:

or pharmaceutically acceptable salt, base, or mixture thereof, wherein nis equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygenatom, the (CH₂)_(n) group having a straight or branched chain, Brepresents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms ora group of the formula

in which R₃ and R₄ may independently be selected from the groupconsisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radicalcontaining 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen,A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenylradical substituted by at least one substituent in the ortho, metaand/or para position, and R₁ represents a hydrogen, or a lower alkyl orhydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleusis attached at the 2-, 3-, or 4-position, wherein administration of thecompound to the discrete site provides a duration of action longer thanthat of lidocaine administration to the discrete site, whereinadministration of the compound alleviates pain experienced by thepatient and provides for improved sleep resulting from the alleviationof pain. 70-75. (canceled)
 76. A method of preparing an S-isomer of acompound of formula 1:

comprising: a) by reacting a compound of formula 2

with an S-enantiomer of a compound of formula 3,

wherein R₁ represents a lower alkyl or hydroxyalkyl containing 1 to 4carbon atoms or a substituted or unsubstituted phenyl and X is a halogen(bromo, chloro, fluoro, iodo) or a reactive esterified hydroxyl group,to form a compound of formula 1; and b) hydrogenating a compound offormula 1, wherein R₁ is a residue removable by means of hydrogenolysisto give a compound of formula 1, wherein R₁ is hydrogen; and c)hydrolyzing a compound of formula 1, wherein R₁ is a residue removableby means of hydrolysis, to form a compound of formula 1, wherein R₁ ishydrogen; and d) transforming free bases obtained into their salts ortransforming salts into their free bases.